Psychotherapy and antidepressant medication are considered first-line treatment options for major depressive disorder (MDD). However, a high proportion of patients do not respond to initial treatment, underlining the need for alternative treatment methods. Repetitive transcranial magnetic stimulation (rTMS) has been established in the treatment of MDD, but the available evidence is limited to forms of MDD with varying degrees of treatment resistance. Randomized-controlled trials (RCT) investigating first-line treatment with rTMS in comparison with first-line antidepressant medication are warranted to further position rTMS within current treatment algorithms for MDD. In this two-stage, therapy response-adapted, randomized multi-center phase 2 rater blinded trial, 106 medication-naïve patients suffering from MDD will be enrolled. In Stage I, participants receive one of the two treatment options for four weeks: either daily bilateral theta burst stimulation (TBS), a patterned and time-saving form of rTMS, or antidepressant medication with selective serotonin reuptake inhibitors (SSRI). The allocation to Stage II occurs therapy response-adapted. Therefore, patients either receive maintenance treatment or will be switched to the respective other treatment arm. Primary outcome is the comparison between the two study arms with regard to therapy response measured by the Montgomery-Asberg Depression Rating Scale (MADRS) after 4 weeks at the end of Stage I. The aim of the study is to provide reliable first evidence and effect size measures of rTMS as first-line treatment compared to SSRI treatment. Positive results will help to implement rTMS in early stages of MDD. Trial registration: ClinicalTrials.gov ID: NCT06545474, August 15, 2024.